Abnormalities in the (3-Adrenergic Receptor ((3AR) signaling system, such as reduction in the number of PARs (downregulation) and diminished contractile response to catecholamine stimulation (receptor desensitization) are hallmarks of heart failure. However, whether changes in PAR signaling represent an adaptive protective process, as some postulate, or whether pAR dysregulation actually promotes deterioration of cardiac function is under considerable debate. Results from our previous studies suggest that chronic PARdownregulation in the failing heart is indeed maladaptive and contributes to the deterioration in cardiac function. We propose to test the hypothesis that abnormalities in pAR signaling promote chronic deterioration in cardiac function by activating deleterious signaling pathways in the failing heart. The overall goal of this proposal is to elucidate the mechanisms by which abnormalities in pARs leads to maladaptation in heart failure. Accordingly the specific aims are:1) To define in vitro, the molecular mechanism(s) by which pARs mediates transactivation of the Epidermal Growth factor Receptor (EGFR) to produce a growth response; 2) To investigate G-protein independent mechanisms of P1ARsignaling by studying the role of Darrestinand individual GRKs on the transactivation of the EGFR by the p1AR; 3) To determine whether in vivo, the subtype of pAR is critical for transactivation of the EGFR in the heart under normal and pressure overload induced heart failure; and 4) To determine the role of specific PAR subtypes in the development of heart failure using knock out mice that lack each of the PAR subtypes. Over the past 5 years we have identified new mechanisms for the activation and inactivation of pAR signaling pathways based on novel protein-protein interactions. This proposal builds on those investigations to advance our understanding of the role PAR dysfunction plays in the development of heart failure.